Lanoline derivatives as penetration enhancing substances

ABSTRACT

Formulation to increase the transdermal permeation of pharmaceutical substances or other biologically active substances, characterized by a content of a penetration enhancing portion of lanoline derivatives on their own or in a mixture with esters of isopropyl alcohol with long-chain fatty acids and/or polyethyleneglycol ethers of fatty alcohols with longer chains, as penetration enhancing substances, as well as a process for their production.

The invention relates to lanoline derivatives on their own or in amixture with polyethyleneglycol ethers of fatty alcohols with longerchains as penetration enhancing substances in formulations containingpharmaceutical substances or other biologically active substances.

Transdermal application offers a series of advantages for a multitude ofpharmaceutical substances or other biologically active substances:

the skin is indefinitely accessible

no change of medium occurs as in the case of oral application

the operation is easy and convenient

a single dosage suffices, rather than repeated daily doses

positive psychological effects are registered

a continuous long-time therapy is possible

the therapy can be interrupted at any time

a constant plasma level can be guaranteed for a prolonged period

a plasma level which is too high initially, as is the case withintravenous application, is avoided, resulting in negligible secondaryaction

the danger of an overdosage or underdosage is less

a controlled release of active substances, particularly of those with alow therapeutic index, is guaranteed.

Some pharmaceutical substances which, owing to their high "first-pass"effect, their low dosage and their high effective potential, wouldotherwise be regarded as ideal, possess, in many cases, such a low skinpermeation that it is not possible to obtain therapeutic plasma values.In the case of all these pharmaceutical substances it is necessary toadd so-called penetration enhancers to the system. Along these lines amultiplicity of substances is described, listed in the following PatentSpefications:

U.S. Pat. No. 4,299,826, U.S. Pat. No. 4,343,798, U.S. Pat. No.4,046,886, U.S. Pat. No. 4,130,643, U.S. Pat. No. 4,405,616, U.S. Pat.No. 4,335,115, U.S. Pat. No. 4,130,667, U.S. Pat. No. 3,903,256, U.S.Pat. No. 4,379,454, U.S. Pat. No. 3,527,864, U.S. Pat. No. 3,952 099,U.S. Pat. No. 3,896 238, U.S. Pat. No. 3 472 931.

In Addition to being able to fulfil their specific function, penetrationenhancing substances must possess the following properties: even whenthey remain on the skin for a long time, at occlusive conditions, theymust be tolerated by the skin, must not produce any allergies and mustbe compatible with the active substances involved.

The enhancers known from the literature can be assigned to variouschemical classes:

1. Primary and secondary alcohols

1.1 Short-chain primary alcohols C₂ to C₈

1.2 Long-chain primary alcohols C₄ to C₁₆

1.3 Secondary alcohols C₃ to C₅

2. Anionic tensides, such as, for example, Na-dodecylsulphate

3. Saturated and unsaturated fatty acids

4. Azones and derivatives (1-alkyl azacycloheptane-2-on, 1-alkylazacycloalkanone)

5. Amides such as N,N-diethyl-3-methyl benzamide (DEET),N,N-diethyl-m-toluamide

6. Alkyl-N, N-dialkyl aminoacetate

7. Macrocyclic ketones and lactones

8. Pyrrolidones

9. Esters such as ethyl acetate, isopropyl myristate, glycerinemonolaurate, diethyl sebacate, propylene glycol esters of saturatedfatty acids

10. Terpenes such as limonene, menthol and cineole

11. Phosphatides

12. Organic acids, such as citric acid, salicylic acid, etc.

13. Cationic tensides or amines.

The existence of such a multitude of different substances of allpossible chemical structures, all said to possess a penetrationenhancing effect, makes a single working mechanism seem unlikely.Various thereof are, therefore, under discussion. mechanisms orcombinations thereof are, therefore, under discussion.

1. The effect of solvents in relation to the active substance and skinlipides.

2. The effects on the lipide structure of the membrane.

3. The effects on the keratine and on the protein structure of the skin.

Bearing in mind both the multitude of interactions taking place withinthe skin and the varying chemical qualities manifested by the activesubstances concerned, the penetration enhancing properties of all theseso-called enhancers in relation to one active substance can only bepredicted with difficulty.

From previous experience it can be said that a penetration enhancingsubstance or a certain mixture only very rarely comply with thecharacteristics required by several pharmaceutical substances orpharmaceutical substance groups.

From JP-A-61024517 a transdermal therapeutic system for diseases ofcirculatory organs is known, comprising a plaster with an adhesivelayer, a penetration enhancing substance, as well as a beta blocker asactive substance. Isopropyl myristate and/or isopropyl lanolate areemployed as penetration enhancers. The advantage of this system is saidto be a long-lasting administration of the beta-blocking agent, withoutirritation of the skin occurring. The active substance reaches the bloodcirculation directly without passing the liver, which means that harmfulside effects are avoided. For production of the system, the penetrationenhancing substance is incorporated into the adhesive layer, which layercontains the beta blocker as active substance.

From FR-A-21 32 130 cosmetic formulation such as sun creams, facial,body or hand creams are known, in particular, as moisturizers. These areemulsions of the "water in oil" type. To stabilize these emulsions,mixtures of lanolates, such as magnesium lanolate, calcium, lithium,zink and aluminium lanolate are used. It is the object of theformulation to achieve improved hydration of the epidermis and improvedprotection thereof. According to example 1, one formulation, forexample, contains magnesium lanolate, alcohol of lanoline, isopropylpalmitate, paraffine oil, almond oil, ozokerit, water andparahydroxybenzoate of methyl. The use of polyethyleneglycol ethers offatty alcohols with longer chains as penetration enhancers intransdermal systems is mentioned, for example, in EP-A-0 189 861, page10, lines 16 to 24. These penetration enhancers are, for instance,polyoxyethylenealkyl ethers selected from alkyl groups with 4 to 20,preferably 10 to 18, carbon atoms, with the addition of ethylene oxide,such as, for example, polyoxyethylene lauryl ether, polyoxyethylenecetyl ether, polyoxyether stearyl ether and polyoxyethylene oleyl ether.The use of substances in combination with lanoline derivates, however,is neither known from this document, nor does this document render thesame obvious.

From WO/A/8700042 transdermal systems with isopropyl myristate aspenetration enhancers for verapamile are known. Accordingly, in example10 of this document, a comparatively good penetration of the activesubstance through the skin was observed by means of pre-treatment of theskin with isopropyl myristate prior to application of the matrixcontaining active substance. A comparison according to example 11 withisopropyl myristate incorporated into the matrix resulted in apenetration enhancing effect that was considerably lower. According toexample 12, with the active substance verapamile a considerablyincreased permeation rate was obtained.

The object of the present invention is to supply penetration enhancingsubstances which are tolerated by the skin, are compatible with theactive substance involved, do not produce allergies, which are, inaddition, easily accessible and economical and, at the same time,possess a penetration enhancing effect on more than one activesubstance.

It has now been discovered, surprisingly, that certain lanolinederivatives have the property of increasing the penetration of certainpharmaceutical substances or active substances through the skin. Thesesubstances are normally employed in the cosmetic industry, to producecreams and lotions.

This object is solved, according to the invention, by employing lanolinederivatives together with polyethyleneglycol ethers of long-chain fattyalcohols as penetration enhancing substances in formulations containingpharmaceutical substances or other biologically active substances.

Preferred lanoline derivatives are selected from the group consisting ofacetylated lanoline, acetylated lanoline alcohol, alcoxylated lanoline,lanoline acid, polyethoxylated lanoline acid, polyethoxylated lanolinealcohol, esters of lanoline acid with short-chain aliphatic alcoholssuch as isopropyl lanolate, polyethyleneglycol ethers of lanolinealcohol and esters of lanoline alcohol with long-chain fatty acids. Inso far as polyethoxylated lanoline derivatives are used, the number ofethylene oxide molecules can lie between 2 and 50.

The linear or branched alcohols with C₁ to C₄ preferably primary orsecondary ones, are suitable, above all, as esters of lanoline acid withshort-chain aliphatic alcohols. Examples of these are methanol, ethanol,n-propanol, n-butanol, isopropanol. The saturated or unsaturated fattyacids, above all, such as lauric acid, palmitic acid and stearic acidare just as suitable as myristic acid, oleic acid and linoleic acid asesters of lanoline alcohol with long-chain fatty acids.

If esters of isopropanol with long-chain fatty acids and/orpolyethyleneglycol ethers of fatty alcohols with longer chains areemployed, as well, in combination with lanoline derivatives, then theforegoing fatty acids are suitable as fatty acid components of thecorresponding isopropanol esters. The alcohols corresponding to theabove-mentioned fatty acids, such as oleyl alcohol, lauryl alcohol,cetyl alcohol and stearyl alcohol, or their polyethyleneglycol ethers,which are obtained from the respective alcohols by means of reactionwith differing molecular masses of ethylene oxide, are suitable astypical fatty alcohols with longer chains. Familiar products are thecondensation products of oleyl alcohol with 2 to 50 moles of ethyleneoxide, of lauryl alcohol with 2 to 40, cetyl alcohol with 2 to 45 andstearyl alcohol with 2 to 100 moles of ethylene oxide.

The penetration enhancing substance consists, preferably, of 1 to100%-wt., above all of 1 to 60%-wt., of a lanoline derivative; and of 0to 99, above all of 30 to 90%-wt, of a polyethyleneglycol ether of afatty alcohol (the sum of the components being equal to 100).

A formulation for the administration of verapamile or lopamile throughthe skin is characterized in that for increasing the transdermalpermeation lanoline derivatives are contained as a penetration enhancingportion, on their own or in a mixture with and/or polyethyleneglycolethers of fatty alcohols with longer chains.

Provided the penetration enhancing substance is used in a therapeutictransdermal system (TTS), the latter consists of a backing layerimpervious to active substances, and, adjacent to this, at least onereservoir containing active substances, in which the penetrationenhancing portion is contained; a device for fixing the system to theskin; and, if necessary, a detachable protective release liner. Thesimplest case consists of a so-called single-layer formulation, in whichthe penetration enhancing substance (together with the active substance)is spread in a preferably self-adhesive matrix provided with aprotective release liner which is dehesive on the side next to the skinand with a covering film on the side away from the skin.

In addition to a single-layer formulation of this sort, in which thepenetration enhancer is incorporated in the preferably self-adhesivematrix from a solution or suspension, the pharmaceutical substance canalso be triturated with the penetration enhancing substances, themixture being applied on a substrate, preferably a piece of bondedfabric or woven fabric or foamed rubber. The substrate is then fixed tothe skin by means of a self-adhesive film.

In addition to this, it is also possible to use a multilayered TTS. Forexample, in such a case the pharmaceutical substance can be placed on asubstrate, either on its own or with part of the penetration enhancingsubstance, which substrate is placed on or in a first adhesive layer,seen from the skin, whereas either the total amount of the penetrationenhancer, or at least a part thereof, is spread in a layer separatedfrom the reservoir, preferably in the adhesive layer of the coveringsheet. The penetration enhancing substances can, thus, be present invarious layers in varying concentrations or amounts.

It has been shown that the substances used as penetration enhancersaccording to the invention can be used both together with thepharmaceutical substance in the usual matrix formulations withself-adhesive properties known to the person skilled in the art as wellas jointly with the pharmaceutical or active substance in a gel, a creamor even an ointment fixed in the therapeutic system, and that these canbe brought direct into contact with the intact skin.

Despite the application being repeated many times, no irritation of theskin could be determined.

The penetration enhancing effect is particularly advantageous with theactive substances Verapamile and Gallopamile. A penetration enhancementof isopropyl myristate from PCT/W087/00042 has been described forVerapamile. The lanoline derivatives used in accordance with theinvention exhibit, however, a much more powerful penetration enhancingeffect for Verapamile, as can be seen in the following examples.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 represents a first embodiment of the invention.

FIG. 2 represents a second embodiment of the invention.

The invention will be illustrated in detail by means of the followingexamples:

A. Single-layer Formulation

The formulations described as "single-layer formulation" refer toself-adhesive matrix formulations with the following TTS design (seefigure):

The self-adhesive matrix (2) is placed on a dehesive protective layer(1), and covered by a covering sheet (3).

SINGLE-LAYER FORMULATION EXAMPLE 1

According to the present invention, a pharmaceutical product with asingle-layer construction of the adhesive matrix containing the activesubstances, is produced as follows:

A pressure-sensitive adhesive mass containing the penetration enhancingcomponents and the pharmaceutical substance, comprising:

0.170 kg polyisobutylene (with a mean molecular weight of 900,000 to1,400,000)

0.202 kg of a solid aliphatic hydrocarbon resin (Trade name: Hercures C,molecular weight ca. 1100)

0.152 kg polyterpene resin

0.072 kg polymer of ethylene oxide HO(CH₂ --CH₂ --O)nH n=200 (PEG 200)

0.072 kg colloidal silica

0.079 kg isopropyl lanolate

0.072 kg isopropyl myristate

0.181 kg Gallopamile

1.200 kg Special boiling point spirit 80-110 as solvent

is applied in such a manner to a protective layer which has beenaluminized on one side and made dehesive on both sides that an adhesivelayer of 82 g/m² is obtained after the solvent has been volatilized.

After the adhesive layer has been covered by an impervious coveringlayer consisting of a polyester, the laminate obtained is divided upinto individual parts in accordance with the therapeutic requirements.

RESULT EXAMPLE 1

Content: 14.80 mg/10 cm² of Gallopamile

Penetration rate (mouse skin): 9.61 mg of Gallopamile/10 cm² /24 h

SINGLE-LAYER FORMATION EXAMPLE 1

Production according to Example 1:

Composition:

0.213 kg polyisobutylene

0.253 kg hydrocarbon resin

0.190 kg polyterpene resin

0.045 kg PEG 200

0.091 kg Aerosile 200

0.050 kg isopropyl lanolate

0.045 kg isopropyl myristate

0.113 kg Verapamile

1.400 kg Special boiling point spirit 80-110

Adhesive layer after the solvent has been volatilized: 74 g/m²

RESULT EXAMPLE 1

Content: 8.4 mg Verapamile/10 cm²

Penetration Rate (mouse skin): 5.71 mg Verapamile/10 cm² /24 h

SINGLE-LAYER FORMULATION EXAMPLE 3

Production according to Example 1.

Composition:

0.213 kg polyisobutylene

0.253 kg hydrocarbon resin

0.190 kg polyterpene resin

0.045 kg PEG 200

0.091 kg Aerosile 200

0.050 kg isopropyl lanolate

0.045 kg polyoxyethylene (10) oleyl alcohol ether

0.113 kg Verapamile

1.300 kg Special boiling range spirit

Adhesive layer after the solvent has been volatilized: 85 g/m²

RESULT EXAMPLE 3

Content: 9.62 mg Verapamile/10 cm²

Penetration rate (mouse skin): 6.14 mg Verapamile/10 cm² /24 h

SINGLE-LAYER FORMULATION EXAMPLE 4

Preparation according to Example 1.

Composition:

0.223 kg polyisobutylene

0.265 kg hydrocarbon resin

0.199 kg polyterpene resin

0.047 kg PEG 200

0.095 kg Aerosile 200

0.050 kg isopropyl lanolate

0.119 kg Gallopamile

1.210 kg Special boiling range spirit 80-110

Adhesive layer after solvent has been volatilized: 75 g/m²

RESULT EXAMPLE 4

Content 8.89 mg Gallopamile/10 cm²

Penetration rate (mouse skin): 5.71 mg Gallopamile/10 cm² /24 h.

To produce further self-adhesive matrix formulations, the substancesindicated in the table are mixed in the form of solutions or suspensionsthereof (solvent or dispersion agent: petroleum spirit), applied to theprotective layer which has been made dehesive by means of a coatingdevice, freed of solvent by heating and lined with the covering sheet.The dry weight of the self-adhesive matrix (FG) is indicated in g/m² inthe tabular outline (T means parts by weight).

The protective layer and the covering layer are the same as in Examples1 to 4.

    __________________________________________________________________________    A. Single layer formulation                                                          Poly-                                                                              hydro-                                                                            poly-  colloidal   penetra-                                                                           pharma-     release                                                                             mouse                  FG* iso- carbon                                                                            terpene                                                                           PEG                                                                              silica                                                                             penetration                                                                          tion ceutic                                                                             content                                                                              24 h  skin                No.                                                                              (g/m.sup.2)                                                                       butelene                                                                           resin                                                                             resin                                                                             200                                                                              200  enhancer                                                                             enhancer                                                                           substance                                                                          (mg/10 cm.sup.2)                                                                     mg/10                                                                               %m.sup.2            __________________________________________________________________________    1  95  23.5 T                                                                             28.0 T                                                                            21.0 T                                                                            5.0 T                                                                            10.0 T                                                                             --     --   A 12.5 T                                                                           11.88  1.72  14.5                2  74  22.3 T                                                                             26.5 T                                                                            20.0 T                                                                            4.8 T                                                                            9.5 T                                                                              lanoline                                                                             --   A 11.9 T                                                                           8.76   2.24  25.5                                            alcohol                                                                       5.0 T                                             3  82  22.3 T                                                                             26.5 T                                                                            20.0 T                                                                            4.8 T                                                                            9.5 T                                                                              lanoline                                                                             --   A 11.9 T                                                                           9.74   3.00  30.8                                            alcohol                                                                       5.0 T                                             4  79  22.3 T                                                                             26.5 T                                                                            20.0 T                                                                            4.8 T                                                                            9.5 T                                                                              5.0 T  --   A 11.9 T                                                                           9.38   2.73  29.1                                            acetylated                                                                    lanoline                                                                      alcohol                                           5  72  22.3 T                                                                             26.5 T                                                                            20.0 T                                                                            4.8 T                                                                            9.5 T                                                                              isopropyl                                                                            --   A 11.9 T                                                                           8.55   4.89  57.2                                            lanolate                                                                      5.0 T                                             6  90  22.3 T                                                                             26.5 T                                                                            20.0 T                                                                            4.8 T                                                                            9.5 T                                                                              PPG-5- --   B 11.9 T                                                                           10.69  5.91  55.3                                            lanoline                                                                      alcohol                                                                       ether                                                                         5.0 T                                             7  91  22.3 T                                                                             26.5 T                                                                            20.0 T                                                                            4.8 T                                                                            9.5 T                                                                              hydroxylated                                                                         --   A 11.9 T                                                                           9.62   3.39  35.2                                            lanoline                                                                      5.0 T                                             8  88  22.3 T                                                                             26.5 T                                                                            20.0 T                                                                            4.8 T                                                                            9.5 T                                                                              lanoline                                                                             --   A 11.9 T                                                                           10.45  5.05  48.3                                            linoleate                                                                     5.0 T                                             9  72  22.3 T                                                                             26.5 T                                                                            19.9 T                                                                            4.7 T                                                                            9.5 T                                                                              Isopropyl-                                                                           --   A 11.9 T                                                                           8.53   4.18  49.0                                            lanolate                                                                      5.2 T                                             10 166 22.3 T                                                                             26.5 T                                                                            19.9 T                                                                            4.7 T                                                                            9.5 T                                                                              isopropyl-                                                                           --   A 11.9 T                                                                           19.67  2.76  14.0                                            myristate                                                                     5.2 T                                             11 87  22.3 T                                                                             Abitol                                                                            19.9 T                                                                            4.5 T                                                                            9.5 T                                                                              isopropyl-                                                                           --   B 11.9 T                                                                           10.31  3.81  37.0                            26.5 T          lanolate                                                                      5.2 T                                             12 79  21.2 T                                                                             25.2 T                                                                            18.9 T                                                                            4.5 T                                                                            9.0 T                                                                              isopropyl-                                                                           --   A 11.3 T                                                                           8.90   3.70  41.6                                            lanolate                                                                      5.9 T                                             __________________________________________________________________________     *FG: weight per unit area                                                     A: verapamile base                                                            B: gallopamile base                                                           polyisobutelene                                                               hydrocarbon resin                                                             polyterpene resin                                                             PEG 200                                                                       colloidal SiO.sub.2 200                                                  

B. Reservoir Formulation (Trituration)

The prescriptions dealt with in B.) refer in each case to thetrituration of pharmaceutical substances with the penetration enhancingsubstances indicated in the table. In order to produce a TTS, thesemixtures are applied to a substrate or carrier in the concentrationsindicated in the table.

The substrate can consist of:

Woven fabric

Bonded fabric

Foam rubber (open-pored).

A sheet of woven fabric, bonded fabric or foam rubber which has beenimpregnated with the triturated mixture is fixed to the skin by means ofa self-adhesive film.

EXAMPLE 13

130 mg of a mixture (trituration) consisting of:

2.0 g Verapamile

1.0 g isopropyl lanolate

1.0 g polyoxyethylene (10) oleyl alcohol ether

1.0 g isopropyl myristate

are applied to a plaster consisting of a self-adhesive covering layerand a central piece of bonded fabric.

Penetration of the pharmaceutical substance through the mouse skin afterapplication:

15.26 mg Verapamile/2.54 cm² /24 h

EXAMPLE 14

53 g of a mixture (trituration) consisting of:

2.0 g Verapamile

1.0 g isopropyl lanolate

are applied to a plaster consisting of a self-adhesive covering layerand a central piece of bonded fabric.

Penetration of the pharmaceutical substance through the mouse skin afterapplication:

6.76 mg Verapamile/2.54 cm² /24 h.

    __________________________________________________________________________    B. Reservoir formulation (trituration)                                              penetration                                                                         penetration                                                                         penetration  trituration    release                                                                              mouse                       drug                                                                             enhancer                                                                            enhancer                                                                            enhancer     amount applied                                                                        drug content                                                                         24 h   skin                     No.                                                                              (g)                                                                              (g)   (g)   (g)   miscellaneous                                                                        mg/2.54 cm.sup.2                                                                      mg/2.54 cm.sup.2                                                                     mg/2.54 cm.sup.2                                                                     %                        __________________________________________________________________________    15 2.5                                                                              --    PEG 200                                                                             --    colloidal                                                                             94     A 31.8 0.53   1.7                                  4.0         silica 0.9                                            16 2.0                                                                              isopropyl                                                                           PEG 200                                                                             1.0   --     260     A 104.0                                                                              2.88   2.8                            lanolate 1.0                                                                        4.0                                                               __________________________________________________________________________

C. Multilayered Formulation

The multilayered formulations described below exhibit the followingconstruction (see FIG. 2):

An adhesive layer (2) is arranged on a dehesively finished protectivelayer (1) on or in which the reservoir (3) is arranged. The reservoir(3) comprises an adhesive sheet, impregnated with both thepharmaceutical substance and a polyethyleneglycol ether of oleylalcohol. The reservoir (3) is backed with a covering layer (5) which iscoated with adhesive (4).

To produce such a system, one proceeds as follows:

The dehesively finished protective layer (1) coated with the adhesive(2) is provided with a sheet of bonded fabric (3). This sheet of bondedfabric is doped with the active substance formulation. Subsequently, thecovering layer (5), coated with adhesive is laminated thereon.

EXAMPLE 18

Production:

A release liner which has been aluminized on one side and rendereddehesive on both sides is coated with a mixture consisting of:

72.1 g polyacrylate adhesive solution

32.2 g polyacrylate basic

6.7 g isopropyl lanolate

in such a manner that once the solvent has been volatilized, a weightper area of 50 g/m^(s) of adhesive layer results (adhesive 2 matrix).

A sheet of bonded fabric which is doped with a mixture consisting ofequal parts of Verapamile and polyoxyethylene (10) oleyl alcohol etheris laid on this adhesive layer.

Concentration of Verapamile in the bonded fabric after doping: 65.3mg/13.85 cm²

The doped bonded fabric and the coated protective layer are covered(laminated) with a pressure-sensitive backing sheet consisting of apolyacrylate matrix with a weight per area of 100 g/m² and a polyestersheet in such a manner that the doped bonded fabric is encompassed bythe two self-adhesive matrices. The laminate obtained is stamped in sucha way that a 1 cm wide adhesive margin free of active substances is leftnext to the bonded fabric.

Mouse skin penetration: 3.78 mg Verapamile/2,54 cm² /24 h

I claim:
 1. Formulation to increase the transdermal permeation ofpharmaceutical substances or other biologically active substances,consisting essentially of a content of a penetration enhancing portionof lanolin derivatives alone or together with polyethylene glycol ethersof fatty alcohols as penetration enhancing substances,whereby thelanolin derivatives are selected from the group consisting of acetylatedlanolin, acetylated lanolin alcohol, alkoxylated lanolin, lanolin acid,polyethoxylated lanolin acid, polyethoxylated lanolin alcohol, esters oflanolin acid with aliphatic alcohols, isopropyl lanolate and esters oflanolin alcohol with fatty acids.
 2. Formulation according to claim 1,wherein the polyethyleneglycol ethers of fatty alcohols are selectedfrom the group consisting of reaction products of oleyl alcohol with2-50 moles of ethylene oxide, lauryl alcohol with 2-40 moles of ethyleneoxide, cetyl alcohol with 2-45 moles of ethylene oxide and stearylalcohol with 2-100 moles of ethylene oxide.
 3. Formulation according toclaim 1, wherein the penetration enhancing substance consistsessentially of 1 to 100%-wt. of a lanoline derivative, and of 0 to99%-wt. of a polyethyleneglycol ether of fatty alcohols, the sum of thecomponents always amounting to 100%wt.
 4. Formulation for theadministration through the skin consisting essentially of verapamile orgallopamile and for increasing the transdermal permeation lanolinderivatives, on their own or in a mixture with polyethyleneglycol ethersof fatty alcohols are contained therein as a penetration enhancingportion; andwhereby the lanolin derivates are selected from the groupconsisting of acetylated lanolin, acetylated lanolin alcohol,alkoxylated lanolin, lanolin acid, polyethoxylated lanolin acid,polyethoxylated lanolin alcohols, esters of lanolin acid with aliphaticalcohols, isopropyl lanolate and esters of lanolin alcohol with fattyacids.
 5. Formulation according to claim 4, wherein said lanolinderivatives, are selected from the group consisting of acetylatedlanolin, acetylated lanolin alcohol, alkoxylated lanolin, lanolin acid,polyethoxylated lanolin acid, polyethoxylated lanolin alcohol, esters oflanolin acid with aliphatic alcohols, and esters of lanolin alcoholswith fatty acids alone or in a mixture with esters of isopropyl alcoholswith fatty acids selected from the group consisting of isopropylisostearate, isopropyl laurate, isopropyl linoleate, isopropylmyristate, isopropyl palmitate and isopropyl stearate with polyethyleneglycol ethers of fatty alcohols selected from the group consisting ofreaction products of oleyl alcohol with 2 to 50 moles ethylene oxide,lauryl alcohol with 2 to 40 moles ethylene oxide, cetyl alcohol with 2to 45 moles ethylene oxide and stearyl alcohol with 2 to 100 molesethylene oxide as penetration enhancing substances for formulationscontaining verapamile or gallopamile.
 6. Formulation according to claim1, consisting essentially of a transdermal therapeutic system. 7.Formulation according to claim 3, wherein the penetration enhancingsubstance consists essentially of 1 to 60%-wt. of a lanolin derivative,and 30 to 90%-wt. of a polyethyleneglycol ether of fatty alcohols, thesum of the components always amounting to 100% wt.